Pembrolizumab (25) – Keytruda®

• Clinical trials
  • The KEYNOTE-061 trial is a completed, multicentre, open-label RCT comparing pembrolizumab with paclitaxel.
  • The KEYNOTE 158 trial is a multicentre, open-label, single-arm Phase II trial that has been ongoing since February 2016.
  • The TAGS trial is a completed, randomised, double-blind, Phase III trial in which trifluridine/tipiracil plus best supportive care (BSC) was compared with placebo plus BSC.

a) Adults with unresectable or metastatic gastric cancer with high-frequency microsatellite instability (MSI-H) or with a mismatch repair deficiency (dMMR) and disease progression during or after prior therapy

• Consequently, a non-quantifiable additional benefit is identified for pembrolizumab in the treatment of adults with unresectable or metastatic gastric cancer with MSI-H or dMMR and disease progression during or after prior therapy.
• Overall, the certainty of the evidence for the established additional benefit is therefore classified as ‘hint’.
• mortality
  • For the endpoint of overall survival, a statistically significant advantage in favour of pembrolizumab compared with paclitaxel is observed.
  • Taking into account the wide confidence interval [0.08; 0.80] and against the background of the small number of patients in the relevant patient population, there is consequently minor precision in the overall survival endpoint.
• Morbidity – Progression-free survival (PFS)
  • There is no statistically significant difference between the treatment groups.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • The morbidity component was not assessed on the basis of symptoms, but exclusively by means of imaging procedures (radiologically determined disease progression according to the RECIST 1.1 criteria).
• Morbidity – Symptoms (assessed using the EORTC QLQ-C30 and EORTC QLQ-STO22)
  • Given the small number of study participants who, following censoring, are included in the analysis within the already small relevant patient population, the presented analyses of the patient-reported endpoints EORTC QLQ-C30 and EORTC QLQ-STO22 are considered unusable.
• Morbidity – Health status (assessed using the EQ-5D VAS)
  • Given the small number of study participants who, following censoring, are included in the analysis within the already small relevant patient population, the presented analyses of the patient-reported endpoint EQ-5D VAS are deemed unusable.
• Health-related quality of life (assessed using the EORTC QLQ-C30)
  • In line with the comments on the symptom and health status endpoints, the event-time analyses submitted by the pharmaceutical manufacturer in the dossier for health-related quality of life are deemed unsuitable for evaluation.
• Side effects – Total adverse events (AEs)
  • Adverse events occurred in almost all participants in the KEYNOTE 061 study.
• Side effects – serious adverse events (SAEs), severe AEs, discontinuation due to AEs
  • No statistically significant differences were observed between the treatment groups for the endpoints SAE, severe AEs and discontinuation due to AEs.
• Side effects – specific AEs
  • Due to the small number of patients in the relevant patient population, the data regarding specific AEs are not interpretable.
• Overall assessment
  • The KEYNOTE 061 study provides results comparing pembrolizumab with paclitaxel in terms of mortality, morbidity, quality of life and side effects for the assessment of pembrolizumab’s additional benefit.
  • Overall, a positive effect is observed for the endpoint of overall survival.
  • Given the small number of patients in the relevant patient population, there is a corresponding minor precision in the overall survival endpoint. Consequently, it is not possible to quantify the extent of the improvement.
  • No usable data are available for the patient-reported endpoints on morbidity (symptoms and health status) and health-related quality of life.
  • The endpoints relating to side effects show neither advantages nor disadvantages for pembrolizumab.
  • Given the small number of patients in the relevant patient population, there is also a corresponding lack of precision in the endpoints relating to side effects.

b) Adults with unresectable or metastatic gastric cancer with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) and disease progression during or after at least two previous treatments

• An additional benefit is not proven.
• For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the pivotal study on pembrolizumab in this therapeutic indication. This is the KEYNOTE 158 trial, which enrolled previously treated patients with advanced (metastatic and/or unresectable) solid tumours.
• The KEYNOTE 158 study is an uncontrolled clinical study. Consequently, this study does not include a control group against which the results of treatment with pembrolizumab could be compared.
• For the benefit assessment, the pharmaceutical manufacturer presents a comparison of individual arms of the KEYNOTE 158 and TAGS studies.
• Due to the lack of randomisation, these comparisons are subject to inherent uncertainty and do not constitute an adequate method of indirect comparison. Furthermore, in the present situation of comparing individual arms, there are no effects for which it can be reliably ruled out that they arise solely as a result of systematic bias due to confounding factors.

Courtesy translation only, please refer to the German original.